Process of preparing hydroxy hydrophenanthrene carboxylic acids and their esters



.ble or triple bonds.

Patented Jan. 25, 1949 PROCESS OF PREPARING HYDROXY HYDROPHENANTHRENE CARBOXYLIC ACIDS AND THEIR ESTERS Karl Miescher, Riehen, and Jules Heer and Jean Ren Billeter, Basel, Switzerland, assignors to Ciba Pharmaceutical Products Inc., Summit,

No Drawing. Application June 29; 1944. Serial No. 542,812. In Switzerland January 10, 1944 12 Claims. 1

It has been found that hydroxy-hydrophenanthrene-carboxylic acids or their derivatives can be obtained when l-keto-hydrophenanthrenes which contain in the 2-position -a functionally transformed carboxyl group in addition to a hydrocarbon radical and in the 'I-position a tree phenolic hydroxyl group or a group convertible into such, are reacted with an organo-metallic compound for the purpose of introducing a hydrocarbon radical into the 1position, the newly formed tertiary hydroxyl group then removed directly or indirectly and, if desired, the functionally transformed carboxyl group in the Z-nosition and/ or the substituent in the 7-position converted into a free carhoxyl and hydroxyl group, respectively and non-aromatic double or triple carbon to carbon bonds hydrogenated at any stage after the reaction with the organo-metallic compound. I

Suitable starting materials for this process are, for example, 1,2,3,4-tetrahydrophenanthrene, 1,2,3,4,9,10 hexahydrophenanthrene or compounds derived from octahydrophenanthrene. These compounds contain in the 1-position a keto group and in the 2-position a hydrocarbon radical such as, for example, a methyl, ethyl, propyl or alkylene radical, and a functionally transformed carboxyl group, for instance, a nitrile or acid amide group,in particular an esterified carboxyl group, such as, for example, a carbornethoxy, carboethoxy, or carboben loxy-group. In addition they have in the '7-position a. free phenolic hydroxyl group or a group which is V convertible into such. The latter may be, for example, a hydroxyl group etherized by methan01, ethanol, phenols, benzyl alcohols, etc. or esterified with organic or inorganic acids, a nitro or an amino group, or a halogen atom. The starting materials may, of course, possess any steric configuration and may also contain further substituents.

In order to introduce hydrocarbon radical-s such as, for example, methyl, ethyl, allyl, ro pyl, benzyl or ethinyl radicals into the l-position, the starting materials are allowed to react as described with the corresponding orga-nometallic compounds, e. g., with organo-magnesium or organo-zinc halides, alkyl or alkinylalkali compounds, etc. The newly formed tertiary hydroxyl group is removed directly or in- Y directly from the tertiary alcohols obtained, if necessary after hydrogenation of side chain dou- V This may happen, for example, with the formation-cf acarbon double bond. To this and water is eliminated directly,

gen, or another ester or ether radical. Subsequently a hydroxyl group changed in this way 7 may be eliminated by thermic decomposition. or by treatment with agents which eliminate acid or alcohol. The elimination of the tertiary hydroxyl group as it is formed e. g. in the mentioned Grignard reaction, can also be efiected directly, if desired, by the action of the Grignard agent at a raised temperature. The removal of the hydroxyl group or of the halogen atom can also be undertaken by reduction, e. g. with the help of hydrogen in the presence of a precious metal catalyst, or also with hydroiodic acid in the presence of glacial acetic acid. The conversion of the functionally transformed carboxyl group in 2-position and/ or of the substituent in '7-position into afree carboxyl or hydroxyl group may be effected with hydrolyzing agents, especially in the case of esters or ethers. For benzyl ethers, for example, reducing agents can also be used. If both substituents in Z and I-position referred to above are converted into a free carboxyl or hydroxyl group, such a conversion may. beeffected in steps and in any desired sequence.

In order to saturate non-aromatic double or triple carbon to carbon bonds, in particular those introduced by eliminating the tertiary hydroxyl group or by allowing to react with unsaturated ougano-metallic compounds, the products are hydrogenated at any stage after the reaction with the organo-metallic compound. For this purpose chemical method-s such as catalytic or electrolytic hydrogenation and nascent hydrogen or biochemical methods may be used.

If an unsaturated radical has been introduced, this multiple bond as well as the double bond formed by the elimination of the tertiary hydroxyl group can be hydrogenated in two different reaction stages. Especially the multiple bond introduced with the unsaturated residue can first of all be saturated with hydrogen, the tertiary hydroxyl group then split off with formation of a double bond and the latter finally hydrogenated.

propionic, butyric, palmitic, stearic and benzoic acids, sulphonic acids, polycarbonic acids or sulphonic-carboxylic acids, and finally of inorganic acids, such as sulphuric and phosphoric acids or carbonic acid and its derivatives. Amongst the ethers the glycosides may be specially mentioned.

The free carboxylic acids may be converted into carboxylic acid salts, such as, for example, the salts of alkalis, alkaline earths or ammonium. If the ester or ether radical in the 7-position contains basic groups, corresponding salts with inorganic acids and also, for example, betaine ester salts can be prepared. Thesalts mentioned find application particularly in aqueous solution or for depot treatment.

The products obtained by this process show funnel with sodium thiosulphate solution and water, and then evaporated down. In this way 7 -methoxy-l ethylidene 2 carbomethoxy 2 phenanthrene obtained in this way is heated surprisingly an extremely high oestrogenic efiect,

both by parenteral and by peroral administration.

,The following examples illustrate the invention without however limiting itin anyway, the parts being by weight. V

Example 1 To a Grignard solution,,prepared from 1 part of magnesium and 12 parts of ethyl bromide in 80 parts of absolute ether, 8 parts of 7-methoxyl-oxo-2-carhomethoxy-2-methyl-1,2,3,4-tetrahy drophenanthrene of the formula in 50 parts of absolute benzene are added as rapidly as possible. After allowing to stand for some time at room temperature, the whole is boiled for several hours under reflux. It is then cooled a d decompos d in the usual way with ice-cold ammonium chloride solution. The product of the reaction is absorbed in ether, the ether- (M. T t. 1 9- 0 C.) is obtained in an exactly analogous manner.

The same compound is also obtained when 7-methoxy-1-oxo 2- carboethoxy 2 methyl- 1,2.3.4-tetrahydrophenanthrene is caused to react wi h a solution of sodium or potassium acetylenide in liquid ammonia .or tertiary amyl alcohol. and the 'l-rnethoxy-1-ethinyl-1-hydroxy-2- carboethoxy-2-methyl-12,3,4 tetrahydrophen- 'anthrene of M. Pt. 133C. (isomeric mixture) which is formed, catalytically hydrogenated (e.

g..in alcoholic solution in .thepresence of platinum) until 2 mols of hydrogen have been absorbed, Two different carbinols saturated in the side-chain are formed, and are separated by frac- -tional crysta lization 7 from alcohol. The one 'carbinol formed me1ts at 149-150 C. and is identical with the compound described in paragraph 2. The other isomer melts at 108-109 C.

One part of the tertiary alcohol, M. Pt. 151- 152 0., described in paragraph 1 is boiled under reflux with 0.05 part of iodine in parts of chloroform. After the elimination of water is complete, the solution is washed in a separating "with 6 parts of potassium hydroxide and 2 parts of water to 200 C. After a short time the oil floating on the surface crystallizes. The whole is then cooled, the mass dissolved in water, a

small quantity 'of undissblved substance extracted with ether and the'aqueousalkaline solution acidified with dilute hydrochloric acid. 7- methoxy l-ethyl 2-carboxy-2-methyl-1,23,4- tetrahydrophenathrenethereby separates out. It is recrystallized'from acetone and melts in the pure state at 225-228 C. 1 part of this acid is heated for a few hours to -190" C. in 5 parts of pyridine hydrochloride. After cooling, water is added and the slightly coloured product which separates out dissolved in ether. The ethereal solution is first washed with dilute hydrochloric acid and water and then'extracted with dilute sodium carbonate and water. On acidifying the alkaline extracts 7-hydroxy-1-ethyl-2-carboxy- Z-methyl-1,2,3,4-tetrahydrophenanthrene of the formula oooH ete. m

separates out as a slightly coloured crystalline powder. After recrystallizing from dilute methanol it melts at 201-203 C.

Instead of hydrolysis of the carbomethoxy and the methoxy group in '7-methoxy-l-ethyl- 2 carbomethoxy-2-methyl-1,2,3,4-tetrahydrophenanthrene in stages, ithese two substituents can be eliminated in one'reaction. For this purpose the substance is heated with a mixture of potassium hydroxide and absolute alcohol (1:2)

ethoxy 2 methyl 5 12,13, 1 -"tetrahydrophenanthrenedsf s'aponified by alkaline fusion at 180-2000. to the'fr'ee carboxylic acid, this acid in the formof a saltin aqueous solution shaken up in hydrogen in thepresence of a nickel cata lyst, and the methoxy group split up from the 7- methoxy- 1 ethyl-2-carboxy-2-methyl-1,2,3,4- tetrahydrophenanthrene by means of, for example, hydrobromic acid.

7 hydroxy 1*- ethyl-2 carboxy-2-methy1- 1,2,3,4-tetrahydrophenanthrene possesses an exceptionally pronounced estrogenic hormone action. It produces, on peroral administration to castrated rats, full oestrus in doses" of 01I5-OL2W and an action lasting for 9 dayswith 59 It may be esterified inthe 7-position, e. g. with propionic acid, stearic acid, benzoic acid or car- Example 2 1 part of 7-methoxy 1-ethylidene-2-carbomethoxy 2 methyl 1,2,3A-tetrahydrophenanthrene obtained as an intermediate product as described in Example 1, is heated in a mixture of 10 parts of potassium hydroxide and parts of ethanol in an iron tube to 200-210 C. for 8 to 1.0 hours. The product ofthe reaction is dissolved in water and the solution acidified, when 7 hydroxy l-ethylidene-Z-carboxy z-methyl- 1,2,3,.4a-tetrahydrophenanthrene of the formula O'H LCGOH is precipitated out. After recrystallization from dilute alcohol it melts at 1'76-182 G. with decomposition.

This compound also surprisingly proves to be highly active in the oestrus test on the castrated rat.

By hydrogenation in aqueous, alcoholic; alkaline solution with the help of a nickel catalyst,

the compound can be converted into 7 hydroxy- 1 ethyl 2 i carboxy-2-methyl-1,2;3A-tetrahydrophenanthrene, described in Example 1.

Example 3' 7 methoxy-1-oxo-2-carbomethoxy-2-metliyl- 1,2,3,4-tetrahydrophenanthrene is allowed to react with methyl magnesium iodide in a manner analogous to that of Example 1. One part of 7- inethoxy l-hydroxy 1,2 dimethyl-a carbomethoxy 123,4 tetrahy'drophenanthrene is heated in a water-bath for a few minutes with 3 parts of anhydrous formic acid. The mixture is diluted with plenty of ether and the formic acid extracted with sodium carbonate solution.- On evaporating down the ether solution 7-methoxy- 1 methylene-2-carbomethoxy-z-methyl-1,23,4- tetrahydrophenantlirene remains which, on recrystallization from isopropyl ether, melts at 97-98 C.

This compound can be hydro enated to 7- methoxy 1,2 dimethyl 2-carbomethoxy-1,2,3,4-

The latter is then converted, by means of potas,

sium fusion into 7-methoxy-1,2-dimethyl-2 carboxy-1,2,3,4-tetrahydrophenanthrene.

One part of the acid named is boiled for 10 hours under reflux in partsv of glacial acetic acid and 25 parts of concentrated hydrochloric acid. The solution obtained from the reaction is poured intowater and. the 7-hydroxy-1,2 -dimethyl 2-carboxy 1',2,3,4 tetrahydrophenam threne of the formula.

K V precipitated, filtered off by suction, washed with water and dried. After recrystallization from dilute alcohol this compound melts at 244 C.

Example 4 A mixture of 1.6 parts of magnesium filings and 0.4 part of magnesium-copper alloy filings are activated with iodine and covered with absolute ether. A mixture of 2 parts of allyl bromide and 10 parts of ether is then added, stirring continually and, after the reaction has started, a mixture dropped in consisting of 12 parts allyl bromide, 150 parts of absolute ether and 10'parts' of 'Z-e't'lroXWZ-oxU-Z carboethoxy-Z-ethyl 1,23,4- tetrahydrophenanthrene. (The latter compound has the formula OZHE ooociu and can be obtained, for example, from 'l-ethoxy- 1-oxo- 2-- carboethoxy 1,2,3,4 tetrahydrophenanthrene by ethyl-ation with ethyl iodide and alka'li ethylate in benzene solution.) After the reaction is complete, the mixture is boiled for another hour in a water-bath, then decomposed with ice and hydrochloric acid, and completely dissolved by the addition of more, ether. The ethereal solution is washed with aqueous hydrochloric acid, sodium carbonate solution and Water, dried and evaporated down. 'l-ethoxy 1 hydroxy-l allyl-Z-carboethoxy 2 ethyl-1,2,3,4-

tetrahydrophenanthrene separates out.

1 part of the latter is boiled under-reflux for 15 minutes with a solution of 2 parts of phosphorous oxychloride in parts of pyridine, then cooled, poured on to parts" of ice, and acidified with concentrated hydrochloric acid. The precipitated product is filtered ofi by suction, washed with hydrcchloric acid, sodium carbonate solution and Water, and crystallized from aqueous methanol.

7-ethoxy-1-allylidene-2 carboethoxy 2 ethyli,2,3,4-tetrahydrophenanthrenc is obtained which can be hydrolysed to 7-l1ydroxy 1-allylidene-2- carboxy-2-ethyl-1,2,3,e tetrahydrophenanthrene of the formula I O2'H6 40 0 on analo'eous to Example'2." 1

Example 1 part. of '7 -ethoxy-1-allylidene-2-carboethoxy- 2-ethyl-1,2,3,4-tetrahydrophenanthrene, which is obtained as an intermediate product in the synthesis .described in Example 4 is hydrogenated in parts of glacial acetic acid using 0.1 part of a 10 percent palladium-charcoal catalyst. In this way 7-ethoxy-1-propyl-2-carboethoxy-2-ethyl-1,2,3,4-

tetrahydrophenanthrene is obtained which can be hydrolysed in stages or in one operation as described in Examples 1 and 2 to l-hydroxy-lpropyl-2-carboxy 2 ethyl 1,2,3,4 tetrahydrophenanthrene of the formula CIHb 0 0 on last two reactions can also be carried out in the reverse order. In this case i-hydroxy-l-propylidene 2 carboxy-Z-ethyl 1,2,3,4 tetrahydrophenanthrene is obtained as intermediate product. a The same final product is also obtained if 7- ethoxy-l-oXo-Z carboethoxy 2 ethyl 1,23,4- tetrahydrophenanthrene is allowed to react with propyl magnesium bromide as described in the above examples.

To obtain aqueous solutions of the oestrogenically active product it is converted, for example,

into its alkali, alkaline earth or ammonium salt, e. g. alkyl ammonium or ethanol ammonium salts.

" Instead of the phenol carboxylic acid itself, its 'l-esters of polycarboxylic acids, sulphonic-carboxylic acids or alkylated aminocarboxylic acids may be used to prepare water-soluble salts. Finally certain glycosides are themselves water soluble.

Example 6 3 parts of 7-methoxy-1-oxo-2-carbomethoxy- 2-methyl-1,2,3,4,9,10-hexahydrophenanthrene of the formula Loooon;

are added all at once to a Grignard solution prepared from 1 part of magnesium in 80 parts of absolute ether and 12 parts of ethyl bromide.

The'mixture is then heated for some time under reflux, and the product of the reaction decomposed by cooling with ice-cooled ammonium chloride solution. The product obtained is dissolved in plenty of ether, washed with dilute hydrochloric acid and'water, and the ethereal solution evaporated down in vacuo. The residue is crude 7- methoxy-l-hydroxy-1-ethyl-2-carbomethoxy- 2-methyl-1,2,3,4,9,IO-hexahydrophenanthrene.

obtained. It melts at C. and produces full oestrus in castrated rats with only 0.3-0.5 administered by mouth.

,The compound used as starting material can be obtained, for example, from 'Z-rnethoxy-l-oXo- 1,2,3,4,9,10-hexahydrophenanthrene via the 2-glyoxalate by elimination of carbon-monoxide and methylation in the 2-position.

Thesame end product is obtained if 7-methoxy- .1-oxo-2-carbomethoxy 2-methy1 octahydrophenanthrene or other corresponding, Z-carboxylic acid derivatives, such as the nitrile, are used as starting materials.

The 7-hydroxy-1-ethyl-2-carboxy 2 methyloctahydrophenanthrene can be converted into active esters, for example, the 7-butyrate, '7- palmitate or 7-benzoate. Ifaqueous solutions or special depot efiects are desired, application in the-form of salts, e. g. alkali, alkaline earth or .ammonium salts is advantageous.

Example 7 -rahydrophenanthrene-2-carboxylic acid, 1 mol of hydrogen being absorbed. It melts at 174 C. (not sharply) and can be converted by boiling in hydrobromic acid or treatment with alcoholic caustic potash at 210 C. into the 7-hydroxy-1,2-diethyl-2 -carboxy-1,2,3,4-tetrahydrophenanthrene which melts at 188-189 C. and has the formula C255 Looon By the methods analogous to those described above the following compounds can be prepared: 7-hydroxy-1-methy1-2-carboxy- 2 ethyl1,2,3,4-

tetrahydrophenanthrene, j A

7-hydroxy-1-propy1-2-carboxy 2 ethyl-1,23,4-

tetrahydrophenanthrene, fI-hydmxy-l rep denw- ;arb? -2t y 1 3,4--tetrahydrophenanthrene, i V 'T-hydroxy-1-ethyl-2-carbOXy-2- propyl 1,2,3,4,-

tetrahydrophenanthrene, '7-hydroxy-1-methyl-2-carboxy-2 -prpyl -1.',-2,8,4e

tetrahydrophenanthrene. fl h -d oxv-1-propy1-2-carboxy 2 -p p ;2,3,

tetrahydrophenanthrene, 'l-hydroxy-1-benzy1-2ecarboxy-zr-methyl-1,23,44,-

tetrahydrophenanthrene. 'l-acetoxy-l-ethyl-2-carboxy 2 methyl-1,23,4-

tetrahydroph'enanthrene, 7-propiony1-1-ethyl-2-carboxy-2 -methyl-1,2,3,4-.-

'tetrahydrophenanthrene, 7-benzoyloxy-l-ethyl 2-carboxyez -methy1-- 1,2,-

8,4-tetrahydrophenanthrene, '7propionyloxy- 1-.ethy1-2 carboxyF2-ethyl-1,2,3,

4,-tetrahydrophenanthrene, 7-benzoyloxy-1-ethy1-2-carboxy- 2 -ethyl-1,2,3,4,-

tetrahydrophenanthrene, I 7-propionyloxy-1-methyl-2-carboxy 2 methyl.-

1,2,3,4-tetrahydrophenanthrene; 7-benzoy1oxy-1-methyl-2-carboxy-2-methyl-1,2,-

3 4-tetrahydrophenanthrene, 'l-hydroxy-l-methyl-Z -carboethoxy 2 methyl- 1,2,3A-tetrahydrophenanthrene, '7 propionyloxy 1 methyl 2 9' carboethoxy-2- methyl-1,2,3,4-tetrahydrophenanthrene,

7 -benzoyloxy- 1 -methyl-2-carboethoxy-2-ethy1- 1,2,3,4-tetrahydrophenanthrene.

3. A compound of the formula 4. A compound of the formula alkyl 40 o 0 .alkyl alkyl alkyl 10 0 0H alkyl alkyl. 0-

5. The '7-hydroxy-1-ethy1-2-:arboxy-2-methyl- 1,2,3,4-tetrahydrophenanthrene of the formula 2,1 1 melting at abo t sci-20s c.

v 6. he i-hydrox'y-1-ethyl2-carbomethoxy-2- methyl-12,3,4-tetrahydrophenanthrene of the 'formula melting at about Bit-88C.

7. The 7methoxy-1-ethyl-Z-carlcoxy-Z rnethyle 1,2,3,4-tetrahydrophenanthrene of the formula derivatives thereof which upon hydrolysis, are

convertible thereinto, the steps of reacting a lketo-hydrophenanthrene which (a), is saturated at least in the le, and 4-positions but is unsaturated in the ring containing the 'Z-position, (b) contains an ester group as one substituent in the 2-position and an alkyl group as another substituent in the 2-position, and (0) contains an etherified phenolic hydroxyl group in the 'Z-pcsition. with a metallo-hydrocarbon compound and treating the resultant produ :t, with a hydrolizing agent whereby the hydrocarbon group of the said compound is selectively introduced into the aforesaid l-position.

9. In a process for the manufacture of av hydroxy-hydrophenanthrene-carboxy1ic acid and derivatives thereof which, upon hydrolysis, are convertible thereinto, the steps of reacting a 1- keto-hydrophenanthrene which (a) is saturated at least in the 1-, 2-, 3- and 4-positions but is unsaturated in the ring containing the 7-position, (1)) contains an ester group as one substituent in the 2-position and a methyl group as another substituent in the 2-position, and (0) contains an etherified phenolic hydroxyl group in the 'l-position, with an alkyl magnesium halide and treating the resultant product, with a hydrolyzing agent whereby the alkyl group of the said halide is selectively introduced into the aforesaid l-position.

10. In a. process for. the manufacture of hydroxy-hydrophenanthrene-carlooxylic acid and derivatives thereof wh ch, upon hydrolysis, are,

convertible thereinto, the steps of reacting a lketo-hydrophenanthrene which (a) is saturated at least in the 1-, 2-, 3- and t-positTons but is unsaturated in the ring containing the 'Z-pcsition, (b) contains an ester group as one substituent in the 2-position and a m-"thyl group as aroiher substituent in the 2-position, and (0) contains an derivatives thereof which, upon hydrolysis, are

convertible thereinto, the steps of reacting a, 1-

keto-hydrophenanthrene which (a) is saturated at least in the 1-, 2-, 3- and 4-positions but is unsaturated in the ringcontaining the 7 -position, (b) contains .an ester group as one substituent in the 2-position and a methyl group as another substituent in the 2-position, and (0) contains an etherified phenolic hydroxyl group in the 7-position, with a metallo-hydrocarbon compound containing an unsaturated hydrocarbon group and treating the resultant product with a hydrolyzing agent, whereby the unsaturated hydrocarbon group of the said compound is selectively introduced into the aforesaid l-position.

12. In a process for the manufacture of a hydroxy-hydrophenanthrene-carboxylic acid nd derivatives thereof which, upon hydrolysis, are convertible thereinto, the steps of reacting a 1- keto-hydrophenanthrene which (a) is saturated at least in the 1-, 2-, 3- and 4-positions but is unsaturated in the ring containing the 7-position, (b) contains an ester group as one substituent in the 2-position and a methyl group as another substituent in the Z-positiori, and (0) contains an etherified phenolic hydroxyl group in the 7-posiition, with an acetylenide and treating the resultant product with a hydrolyzing agent, whereby the acetylene group of the said acetylenide is selectively introduced into the aforesaid l-position.

' KARL MIESCHER.

JULES HEE IR. JEAN RENE BILLETER.

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